?We designed an experiment to understand the interactions between loss of development of new neurons (neurogenesis) in the brain, HIV-1 Tat protein, and the known cognitive side-effects imparted by chronic highly active antiretroviral therapy (HAART). We preliminarily found the common HAART combination for HIV patients ,lamivudine/zidovudine/efavirenz (3TC/AZT/EFV): (1) reduced primary neural stem cell proliferation in vitro (2) increased NSC mitochondrial oxidative stress and that these could be opposed in vitro by NutraStem(r). We also show this regimen decreases hippocampal neurogenesis in vivo. We hypothesize NutraStem(r) will oppose HAART and Tat mediated neurogenesis pathology by reducing the effect of these two components on mitochondrial stress, in turn promoting neurogenesis, and reducing neurocognitive deficits in HIV-1 Tat transgenic mice. Here we plan to characterize neurocognition, and neurogenesis in HIV-1 Tat mice chronically treated with HAART. EFV or EFV/3TC/AZT should lead to advanced neurocognitive deficits in these mice that should be enhanced by brain HIV-1 Tat expression which that can be correlated with decreases in neurogenesis, compared to control AZT, or 3TC treated mice. NutraStem(r) should attenuate this phenomenon. We expect that other indicators of this NutraStem(r) mediated neuroprotection will include a reduction of memory problems which will be tested and brain mitochondrial stress in the Tat/HAART exposed mice. This study is expected to describe the long-term consequences of chronic Tat expression with use of a common HAART regimen plus a neuroprotectant (NutraStem(r)) in terms of neurogenesis and cognitive deficits. It should lay the foundation for effective strategies to prevent these interactions between Tat, HAART, and neurogenesis in the future in the context of a known HAART-mediated pathophysiological mechanism.
Public Health Relevance Statement: Public Health Relevance: Neurocognitive deficits have been associated with decreased adherence among HIV-positive adults. They have also been positively correlated with Tat mediated reduced neurogenesis in the brain as well as chronic HAART use. These trends underscore the need for a better understanding of the impact of a need for a neuroprotectant in HAART treated patients. This is especially true as patients with HIV are now aging; itself being a risk factor neurodegenerative disease . Our proposal addresses these trends by examining the synergistic effects of Tat, cognitive impairment, and chronic HAART administration on reduced hippocampal neurogenesis in a transgenic HIV-1 Tat expressing mouse model.
NIH Spending Category: Acquired Cognitive Impairment; Basic Behavioral and Social Science; Behavioral and Social Science; Brain Disorders; Complementary and Alternative Medicine; HIV/AIDS; Infectious Diseases; Mental Health; Neurodegenerative; Neurosciences; Prevention; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human
Project Terms: Accounting; Address; Adherence (attribute); Adult; Adverse effects; Affect; Age-Months; Aging; Atrophic; Attenuated; Autopsy; base; Behavioral; Blood Circulation; Brain; Cell Proliferation; cell type; Cells; Chronic; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; dentate gyrus; design; Detection; Development; efavirenz; Excision; experience; Foundations; Functional Magnetic Resonance Imaging; Future; Highly Active Antiretroviral Therapy; Hippocampus (Brain); HIV; HIV Infections; HIV Seropositivity; HIV tat Protein; HIV-1; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; in vivo; Individual; Infection Control; Lamivudine; Lead; Learning; Mediating; Mediator of activation protein; Memory; Messenger RNA; Mind; Mitochondria; mouse model; Mus; nerve stem cell; Neurocognition; Neurocognitive; Neurocognitive Deficit; neurocognitive test; Neurodegenerative Disorders; neurogenesis; Neurons; neuroprotection; Neuroprotective Agents; neurotoxic; neurotoxicity; non-nucleoside reverse transcriptase inhibitors; novel; object recognition; Oxidative Stress; Parahippocampal Gyrus; Pathology; Patients; Peripheral; Population; Prevalence; prevent; Prevention; Process; Production; public health relevance; Reactive Oxygen Species; Regimen; relating to nervous system; research study; respiratory; Risk Factors; Short-Term Memory; stem cell population; Stress; Task Performances; tat Protein; Testing; Transgenic Mice; Transgenic Organisms; trend; Viral; Viral Load result; virtual; Virus; Zidovudine
